Discovery and validation of biomarkers of autoimmunity in Alzheimer's Disease.

阿尔茨海默病自身免疫生物标志物的发现和验证。

• 批准号: 10589569
• 负责人: ELEFTHERIOS P DIAMANDIS
• 金额: $ 13.82万
• 依托单位: SINAI HEALTH SYSTEM
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-15 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10589569
• 关键词: Affect; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Alzheimer' s disease therapy; Alzheimer’s disease biomarker; Amyloid; Antibodies; Antigen-Antibody Complex; Antigens; Applications Grants; Autoantibodies; Autoantigens; Autoimmune; Autoimmunity; Biological; Biological Assay; Biological Markers; Biostatistical Methods; Brain; Central Nervous System; Cerebrospinal Fluid; Clinical; Clinical Trials; Clinical Trials Design; Cognitive; Collaborations; Complex; Dementia; Diagnosis; Diagnostic; Differential Diagnosis; Disease; Disease Management; Disease Progression; Enzyme-Linked Immunosorbent Assay; Future; G-substrate; Genetic; Goals; Hybrids; IgG autoantibodies; Immune; Individual; Industrialization; Inflammation; Investments; Liquid substance; Mass Spectrum Analysis; Measurement; Methodology; Methods; Monitor; Neurodegenerative Disorders; New Agents; Parkinson Disease; Pathogenesis; Patients; Persons; Phase; Prevention; Process; Prognostic Marker; Proteins; Proteome; Proteomics; Reaction; Recombinant Proteins; Role; Sampling; Serology test; Serum; Severities; Shotguns; Spain; Symptoms; Synapses; Technology; Testing; Therapeutic Agents; Time; Validation; Variant; accurate diagnosis; assay development; biobank; biomarker identification; biomarker validation; candidate identification; coronavirus disease; design; diagnostic biomarker; diagnostic value; early phase clinical trial; effective therapy; experimental study; falls; magnetic beads; mild cognitive impairment; neuroinflammation; neuron loss; neuropathology; novel; novel therapeutics; patient response; prognostic value; vaccine trial

R21 Project summary abstract Alzheimer’s disease is a serious neurodegenerative disorder affecting millions of people. Currently there are no effective therapies and the reliance on managing the disease depends on accurate diagnosis and assessment of progression. In our grant application we aim to identify biomarkers for differential diagnosis between Alzheimer’s disease and other neurodegenerative disorders and also, biomarkers that are able to non-invasively assess the progression of the disease. We postulate that Alzheimer’s disease is pathogenesis is multifactorial and includes the classical amyloid hypothesis and other, evolving hypotheses. We postulate that at least some patients develop AD due to autoimmune reactions between autoantibodies present in cerebral spinal fluid (CSF) against brain specific proteins. Our preliminary studies have clearly shown that some patients with Alzheimer’s disease possess either autoantibodies or autoimmune complexes in cerebral spinal fluid. By using state-of-the-art mass spectrometry we will identify such autoantibodies or immune complexes in a discovery phase, using a highly sensitive and specific assay that we recently developed. Once we identify candidate molecules in cerebral spinal fluid we will collaborate with a company, MesoScale Diagnostics, to develop targeted assays for about10 autoantibodies/immune complexes that can be assessed first in cerebral spinal fluid and later in serum. In association with an excellent biobank in Barcelona Spain (collaborator Dr. Morato) we will obtain high quality samples with clinical annotations from patients without Alzheimer disease, with mild moderate and sever Alzheimer disease and patients who have progressive or non-progressive disease. By using these valuable samples we will do the discovery experiments the first year followed by targeted assay development in the second year. Once we complete these objectives we intend to mound an extensive validation process to identify a group of autoantigens/immune complexes that can be used for differential diagnosis and monitoring of AD disease progression. We believe that our discovered biomarkers will be fundamental in clinical trials which are testing new agents which may be able to slow down or halt the disease at an early stage.

R21项目总结摘要 阿尔茨海默病是一种严重的神经退行性疾病，影响数百万人。目前有 没有有效的治疗方法，对疾病的控制依赖于准确的诊断和 进展评估。在我们的拨款申请中，我们的目标是识别用于鉴别诊断的生物标志物 阿尔茨海默病和其他神经退行性疾病之间的关系，以及能够 非侵入性评估疾病的进展。我们假设阿尔茨海默病是 发病机制是多因素的，包括经典的淀粉样蛋白假说和其他不断发展的假说。 我们假设至少有一些患者由于自身抗体之间的自身免疫反应而患上 AD 存在于脑脊液 (CSF) 中，对抗大脑特定蛋白质。我们的初步研究有 清楚地表明一些阿尔茨海默病患者具有自身抗体或自身免疫 脑脊液中的复合物。通过使用最先进的质谱分析法，我们将识别这样的 处于发现阶段的自身抗体或免疫复合物，使用我们的高度灵敏和特异性的检测方法 最近开发的。一旦我们确定了脑脊液中的候选分子，我们将与 MesoScale Diagnostics 公司将开发约 10 种自身抗体/免疫复合物的靶向检测方法 可以首先在脑脊液中进行评估，然后在血清中进行评估。与优秀的生物样本库合作 西班牙巴塞罗那（合作者莫拉托博士）我们将获得带有临床注释的高质量样本 无阿尔茨海默病患者、轻度、中度和重度阿尔茨海默病患者以及患有阿尔茨海默病的患者 进行性或非进行性疾病。通过使用这些有价值的样本，我们将进行发现 第一年进行实验，第二年进行有针对性的分析开发。一旦我们完成 这些目标我们打算建立一个广泛的验证过程来确定一组 可用于 AD 疾病鉴别诊断和监测的自身抗原/免疫复合物 进展。我们相信，我们发现的生物标志物将成为临床试验的基础，这些试验正在测试 新药物可能能够在早期阶段减缓或阻止疾病。